Two novel camp-specific phosphodiesterase (pde4b)isoforms and related technology

ABSTRACT

Two novel cAMP-specific isoforms of rat PDE4B are disclosed. pRPDE90 is a cDNA encoding a 659-amino acid-long protein with a large region corresponding to similar regions found in PDE4B1 and PDE4B3. It is separated from these isoforms by a 17-amino acid region found at its extreme amino-terminal end which shows no homology to any previously-cloned sequence. pRPDE89 is a rat cDNA which encodes a 726-amino acid-long protein which is 96% identical to the human PDE4B1 phosphodiesterase isoform.

RELATED APPLICATIONS

[0001] This application is related to and claims the benefit of U.S.Provisional Application Serial No. 60/170,562 of Graeme B. Bolger, filedDec. 14, 1999 and entitled “Two Novel cAMP-Specific Phosphodiesterase(PDE4B) Isoforms and Related Technology,” which is incorporated hereinby reference.

FIELD OF THE INVENTION

[0002] The present invention relates to cyclic AMP-specificphosphodiesterases (PDE4 enzymes), which help regulate physiologicalprocesses by hydrolizing cAMP, an intracellular signaling molecule.Specifically, the invention relates to two novel cAMP-specificphosphodiesterase isoforms which are expressed in many body tissues,including the brain.

TECHNICAL BACKGROUND

[0003] Cyclic AMP (“cAMP”) is an intracellular signaling moleculeinvolved in many important cellular processes. Specifically, cAMP iscritical to signaling pathways which regulate physiological processessuch as those involved in vascular smooth muscle, the immune system, andthe brain. cAMP-specific phosphodiesterases, referred to as “PDE4enzymes,” hydrolyze cAMP and thus regulate these pathways in cells. ThecAMP-specific phosphodiesterases can be differentiated from other cyclicnucleotide phosphodiesterase (“PDE”) families by sequence homology inthe catalytic region of the proteins as well as by their ability to beinhibited by a specific class of drugs, such as rolipram. Beavo,Physiol. Rev. 75:725-48 (1995). Rolipram and other specific PDE4inhibitors have anti-depressant, anti-inflammatory and smooth musclerelaxant properties in humans. Houslay et al., Advances in Pharmacology,44:225-342 (1998). PDE4 enzymes are also characterized by the presenceof unique “signature” regions of sequence, called upstream conservedregions, or “UCR,” such as UCR1 and UCR2, which are located in theamino-terminal third of the proteins. Houslay, et al., supra; Bolger etal., Mol. Cell Biol., 13:6558-71 (1993).

[0004] PDE4 enzymes are also the closest vertebrate homologs of thedunce gene of Drosophila melanogaster, which was isolated as a mutationaffecting learning and memory. Davis, Physiol. Rev. 76:299-317 (1996).The mammalian PDE4s are encoded by four genes (PDE4A, PDE4B, PDE4C andPDE4D), and it has been shown by several researchers that additionaldiversity in this family is produced by alternative mRNA splicing.Bolger et al., supra; Sette et al., J. Biol. Chem., 269(32):20806 (Aug.12, 1994); Bolger et al., J. Biol. Chem., 271:1065-71 (1996); Bolger etal., Biochem. J., 328:539-48 (1997); Naro et al., Endocrinology,137:2464-72 (1996); Huston et al., Biochem J. 328:549-56 (1997). SeeHouslay et al., supra, for a review of these findings. Often thealternatively-spliced isoforms have different tissue expressionpatterns, a fact which suggests that each may have a distinct function.

[0005] Intracellular signaling molecules are important since theytransmit a signal received outside of the cell to target molecules inthe cytosol, thus allowing a cell to react to changes in itsenvironment. This transmission is generally a multistep process oftenhaving at least the general steps laid out in the followingcAMP-specific sequence: First, an extracellular ligand binds to a plasmamembrane-bound receptor molecule which has a binding domain extendinginto the extracellular space and a domain extending into the cytosol.Second, the binding of the ligand to the extracellular domain changesthe conformation of the cytosolic domain, thus causing it to bind to aG-protein. Third, the G-protein, in turn, activates a plasma membraneenzyme which produces cAMP (adenylyl cyclase). Fourth, the cAMP thenbinds to target molecules in the cytosol, thus altering theirconformation and activity. Finally, cyclic AMP-specificphosphodiesterases rapidly break down the cAMP, hydrolizing it to formadenosine 5′-monophosphate.

[0006] As seen in the final step, in order to use cAMP as a signalingmolecule, a cell must be able to quickly manipulate the levels of cAMPpresent in response to signals transmitted to the outside of the cell.Cyclic AMP functions well in this respect, having been shown in somecases to respond to hormonal stimulation by increasing in cellularconcentration by five-fold within seconds.

[0007] Such rapid changes in cAMP levels are possible due to a cell'sability to rapidly synthesize cAMP. Cells are also adapted to rapidlybreak down cAMP. Cyclic AMP is synthesized from ATP by adenylyl cyclase,an enzyme found in the plasma membrane of a cell. Cyclic AMP ishydrolized by cyclic AMP phosphodiesterases to form adenosine5′-monophosphate (“5′-AMP”). These phosphodiesterases are found in manytissues, including specific regions of the brain.

[0008] It is known that certain cAMP-specific phosphodiesterases (“PDE4enzymes”) are the targets of inhibitors. Some of these inhibitors havebeen shown to have positive effects on the brain, including exhibitinganti-depressant properties, memory-enhancing qualities, and otherpositive effects on the function of the central nervous system.Unfortunately, however, these beneficial effects are often accompaniedby nausea and other gastrointestinal side effects. These negative sideeffects are likely mediated at least in part by the action of theinhibitors used on the brain. The number of isoforms of the PDE4 enzymespresent in the brain is currently unknown, as is an understanding ofwhich inhibitors affect which phosphodiesterases. Knowledge of novelisoforms of PDE4 enzymes would be a great advancement in the art,allowing researchers and health professionals to learn to target PDE4inhibitors to specific isoforms and limit the effects of the inhibitionto the desired, positive effects, while avoiding inhibition of thoseisoforms whose inhibition causes the deleterious side effects notedabove.

[0009] From the foregoing, it will be appreciated that it would be anadvancement in the art to identify additional PDE4 enzyme isoforms. Suchidentification would enable investigation of the patterns of isoformtissue expression, and thus allow selective targeting of specificisoforms with isoform-specific inhibitors, yielding effective use of thebeneficial effects of inhibition while avoiding the deleterious ones.

[0010] Such novel PDE4 enzyme isoforms are disclosed herein.

BRIEF SUMMARY OF THE INVENTION

[0011] The present invention relates to isoforms of cAMP-specificphosphodiesterase. Specifically, two rat cDNAs, pRPDE89 and pRPDE90,were isolated from a rat cerebral cortex cDNA library. Both of thesewere found to encode novel PDE4B isoforms. The invention thus comprisesa first cDNA, pRPDE89, which encodes a protein identical in length tothat encoded by the previously-described human PDE4B1 isoform known inthe art. The protein encoded by both the rat and human genetic materialis 736 amino acids in length. This rat cAMP-specific phosphodiesteraseisoform is over 96% identical in sequence to the human PDE4B1 isoform.

[0012] The invention further comprises a second cDNA, pRPDE90, whichencodes a novel protein of 659 amino acids, called PDE4B4. PDE4B4 has anovel N-terminal region of 17 amino acids which is not present in anyother known PDE4B isoform. The remaining 642 amino acids of PDE4B4 areidentical to those found in corresponding regions of the PDE4B1 andPDE4B3 isoforms. Without being bound to any particular theory, it isbelieved that the structures of the cDNAs encoding the PDE4B1, PDE4B3,and PDE4B4 isoforms are generated by alternative mRNA splicing andthrough the use of alternative promoters of the PDE4B gene. RNaseprotection and immunoblotting demonstrated the presence of mRNA andprotein specific for each of the PDE4B1, PDE4B2, PDE4B3 and PDE4B4isoforms, respectively, in a wide range of tissues, including variousregions of the brain.

[0013] Since various inhibitors of cAMP phosphodiesterases have beenshown to have anti-depressant and memory enhancement effects, thediscovery of novel isoforms of PDE4B opens possibilities of betterunderstanding and targeting such inhibitors to have more selectiveeffects on the brain.

[0014] These and other features of the present invention will becomeapparent upon reference to the accompanying figures and upon reading thefollowing detailed description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] A more particular description of the invention briefly describedabove will be rendered by reference to the appended figures. Thesefigures only provide information concerning typical embodiments of theinvention and are not therefore to be considered limiting of its scope.

[0016]FIG. 1 shows the structure of mRNAs encoded by the rat PDE4B gene.The numbers 1-4 indicate transcripts represented by the following cDNAs:1, PDE4B1 (pRPDE89 (SEQ ID NO: 5); GenBank™ AF202732); 2, PDE4B2(pRPDE18 (SEQ ID NO: 8); GenBank™ L27058); 3, PDE4B3 (pRPDE74 (SEQ IDNO: 9); GenBank™ U95748); 4, PDE4B4 (pRPDE90 (SEQ ID NO: 1) and pRPDE92(SEQ ID NO: 10); GenBank™ AF202733). The heavy bar indicates sequenceshomologous to other PDE4 isoforms, with the strongest regions ofconservation (the catalytic region and UCR1 and UCR2) indicated by thecross-hatched areas. The thin, branched lines adjacent to the numbersindicate sequence regions unique to each isoform. The thin lines mergewhere the sequences of the various isoforms join the shared sequence.Small boxes indicate start codons and the asterisk indicates the commonstop codon.

[0017]FIG. 2 shows an alignment of the amino acid sequences of humanPDE4B1 (top, SEQ ID NO: 7) and rat PDE4B1 (bottom, SEQ ID NO: 6). Thesequence of human PDE4B1 has been described previously (pTM72 in Bolger,Mol. Cell Biol. 13:6558-71 (1993), GenBank™ L20966). The sequence ofPDE4B1 was deduced from the pRPDE89 cDNA.

[0018]FIG. 3 shows an alignment of the amino acid sequences of ratPDE4B1 (SEQ ID NO: 6), PDE4B2 (SEQ ID NO: 8), PDE4B3 (SEQ ID NO: 9), andPDE4B4 (SEQ ID NO: 2). The sequences are derived from the followingcDNAs: PDE4B1 (pRPDE89 (SEQ ID NO: 5); GenBank™ AF202732); PDE4B2(pRPDE18 (SEQ ID NO: 10); GenBank™ L27058); PDE4B3 (pRPDE74 (SEQ ID NO:11); GenBank™ U95748); PDE4B4 (pRPDE90 and pRPDE92; GenBank™ AF202733).

[0019]FIG. 4 shows the nucleotide sequence (SEQ ID NO: 1) encodingPDE4B4. The sequences of two plasmids, pRPDE90 and pRPDE92, have beenmerged. On the merged sequence, pRPDE92 corresponds to nucleotides 1 to1936, and pRPDE90 corresponds to nucleotides 253 to 2433. This sequenceis available as GenBank™ AF202733.

[0020]FIG. 5 shows the nucleotide sequence of pRPDE89 (SEQ ID NO: 5),which encodes PDE4B1. This sequence is available as GenBank™ AF202732.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides two novel cAMP-specificphosphodiesterase (PDE4B) isoform cDNAs. These cDNAs encodephosphodiesterases, which function in the regulation of physiologicalprocesses by hydrolizing cAMP, an intracellular signaling moleculederived from ATP.

[0022] The first cAMP-specific phosphodiesterase isoform cDNA ispRPDE90, a phosphodiesterase isolated from a rat (Rattus norwegenesis;Sprague-Dawley strain) cerebral cortex cDNA library cloned into the EcoRI site of Lambda ZAPII, which was obtained from Stratagene. This cDNAencodes a novel PDE4B isoform named PDE4B4 by the inventors inaccordance with convention.

[0023] PDE4B4 is a novel PDE4B isoform comprising 659 amino acids, 642of which are shared with the other “long;” isoforms of PDE4B: PDE4B1 andPDE4B2. The remaining 17 amino acids are found at the extremeamino-terminal end of the protein.

[0024] The second cAMP-specific phosphodiesterase isoform cDNA of theinstant invention is pRPDE89, a novel rat cDNA. pRPDE89 encodes aprotein comprising 736 amino acids. This protein is identical in lengthand 96% identical in amino acids to the human PDE4B1 isoform (712 of 736amino acids are identical). Without being bound to any particulartheory, it appears that pRPDE89 encodes the rat counterpart of the humanPDE4B1 isoform of PDE4B.

[0025] The present invention provides isolated and purified nucleic acidmolecules comprising nucleotides that encode the amino acid sequences ofSEQ ID NOS: 2, 4, and 6. In certain embodiments, these nucleic acidmolecules comprise nucleotides 262 to 2238 of SEQ ID NO: 1, nucleotides1 to 51 of SEQ ID NO: 3, and nucleotides 325 to 2532 of SEQ ID NO: 5,respectively. The present invention also provides nucleic acid moleculesthat encode amino acid sequences that are greater than 90%, greater than85%, greater than 80%, greater than 75%, and greater than 70% identicalto SEQ ID NO: 4. The present invention also provides such nucleic acidmolecules subcloned into plasmids; such nucleic acid molecules subclonedinto prokaryotic or eukaryotic expression vectors; and such nucleic acidmolecules stably or transiently incorporated into a prokaryotic oreukaryotic host cell.

[0026] The present invention also provides isolated and purifiedproteins comprising the amino acid sequences of SEQ ID NOS: 2 and 6 andpeptides comprising the amino acid sequence of SEQ ID NO: 4. The presentinvention further provides antibodies that specifically recognizepeptides comprising the amino acid sequence of SEQ ID NO: 4. Suchantibodies may be polyclonal or monoclonal antibodies that are preparedaccording to methods that are well-known in the art. See, e.g., Harlow &Lane, Antibodies: A Laboratory Manual (1988).

[0027] Novel PDE4B isoforms such as those of the instant invention areof importance for several reasons. One reason is that the isoforms ofthe present invention are expressed in brain—an important potentialtarget of PDE4 inhibitors. Indeed, cDNAs encoding numerous PDE4 isoformshave previously been isolated from brain. See e.g., Bolger et al., Mol.Cell Biol. 13:6558-71 (1993), Huston et al., Biochem J. 328:549-56(1997), McLaughlin et al., J. Biol. Chem. 268:6470-76 (1993), Bolger etal., Gene. 149:237-44 (1993), Davis et al., Proc. Natl. Acad. Sci.U.S.A. 86:3604-08 (1989), Colicelli et al., Proc. Natl. Acad. Sci.U.S.A. 86:3599-3603 (1989), and Engels et al., FEBS Lett. 358:305-10(1995). The brain is thus a target for many of the actions of selectivePDE4 inhibitors. It is therefore important to determine exactly whichPDE4 isoforms are present in the brain.

[0028] PDE4 inhibitors have several demonstrated effects in the humanbrain, several of which are beneficial, and others of which are harmful.Some of the potential beneficial effects of PDE4 inhibitors include ademonstrated anti-depressant action. Fleischhacker et al.,Neuropsychobiology, 26:59-64 (1992), Eckmann et al., Current TherapeuticResearch, 43:291-95 (1988). PDE4 inhibitors may also augment memory andother central nervous system functions. However, PDE4 inhibitors cancause nausea and trigger other gastrointestinal side effects. At least aportion of these deleterious side effects are likely mediated by theaction of these drugs in the brain.

[0029] Discovery of additional isoforms of the PDE4B phosphodiesteraseswould open greater possibilities for developing inhibitors that could bespecifically targeted at one or more isoforms. Such targeting wouldallow a more viable approach for utilizing the beneficial properties ofthese inhibitors in clinical treatment, while selectively avoidingnegative side effects.

[0030] As a result, a search for novel PDE4 isoforms was initiated inrat brain. Two previously unknown PDE4 isoforms were subsequentlyisolated. While not being bound to any one particular theory, one ofthese appears to be the rat homolog of the human PDE4B 1 isoform, whichhas been described previously in the art. Bolger et al., Mol. Cell Biol.13:6558-71 (1993). The second novel isoform, called PDE4B4, has a unique17 amino acid amino-terminal region which is not present in any otherPDE4B isoform. It appears likely that PDE4B4 will be similar to otherPDE4 isoforms in that it will be highly specific for cAMP and beinhibited by the prototypical PDE4 inhibitor rolipram.

[0031] It has previously been shown that the various PDE4 isoforms havedifferent tissue expression patterns. Huston et al., Biochem J.328:549-56 (1997). Indeed, it has even been shown that differentisoforms encoded by the same gene may vary substantially in their tissueexpression. (Bolger et al., Mol. Cell Biol. 13:6558-71 (1993), Bolger etal., J. Bio. Chem. 271:1065-71 (1996), and Bolger et al., Gene.149:237-44 (1994). Studies are in progress to determine the pattern ofexpression of the four known rat PDE4B isoforms, with special emphasison their expression in various regions of the brain. Such discoveriesand studies create the possibility of exploiting differences in thepatterns of tissue expression of the various PDE4 isoforms to “target”the effects of PDE4 inhibitors to specific regions of the brain, thusmaximizing their positive effects and minimizing or negating theirnegative effects.

[0032] One current explanation for the divergence of the PDE4B1, PDE4B3and PDE4B4 mRNAs is alternative mRNA splicing. This has been documentedas accounting for the existence of the PDE4A and PDE4D isoforms. Bolgeret al., J. Biol. Chem. 271:1065-71 (1996), Bolger et al., Biochem J.328:539-48 (1997), and Houslay et al., Advances in Pharmacology44:225-342 (1998). Consistent with this explanation, it has been shownthat the point of divergence between PDE4B1, PDE4B3 and PDE4B4corresponds with the major point of alternative mRNA splicing in the D.melanogaster dunce gene transcripts. It also corresponds with the majorpoint of alternative mRNA splicing in alternatively spliced mRNAs fromthe human PDE4A (Bolger et al., Mol. Cell Biol. 13:6558-71 (1993)),PDE4B (Huston et al., Biochem J. 328:549-56 (1997)) and PDE4D (Bolger etal., Biochem J. 328:539-48 (1997)) genes. It also corresponds to the 5′end of an exon in the human PDE4A (Sullivan et al., Biochem J.333:693-703 (1998)) and murine Pde4a (Olsen & Bolger, Mammalian Genome11:41-45 (2000)) genes.

[0033] In addition, since there is no common 5′ region of sequence atthe 5′ ends of any of these cDNAs, it appears likely that each isgenerated from a different transcriptional start site. It has beenpreviously demonstrated that several murine Pde4a transcripts, includingPDE4A5, are generated in this manner (Olsen & Bolger, Mammalian Genome11:41-45 (2000)).

[0034] All references, publications, patents, patent applications, andcommercial materials cited in this application are hereby incorporatedby reference in their entirety.

EXAMPLES

[0035] The following example is given to illustrate an embodiment whichhas been made within the scope of the present invention. It is to beunderstood that the following example is neither comprehensive norexhaustive of the many types of embodiments which can be prepared inaccordance with the present invention.

Example 1—Two Novel PDE4B Isoforms

[0036] Experimental Techniques:

[0037] Materials: A rat (Rattus norwegenesis; Sprague-Dawley strain)cerebral cortex cDNA library, cloned into the Eco RI site of LambdaZAPII, was obtained from Stratagene. All molecular biology, biochemistryand cell culture reagents were from New England Biolabs, LifeTechnologies or Roche Molecular Systems unless specified otherwise.

[0038] Isolation and Analysis of cDNA Clones: Procedures were asdescribed by Sambrook et al. (Sambrook et al., Molecular Cloning: ALaboratory Manual, (1989)) unless otherwise specified. The cDNA librarywas screened with a probe corresponding to nucleotides 204 to 1299 ofrat PDE4B3 (pRPDE74 (SEQ ID NO: 9) GenBank™ accession number U95748;(Huston et al., Biochem J. 328:549-56 (1997)). This region encodes theunique amino-terminal region of PDE4B3 as well as UCR1 and the majorityof UCR2 (FIG. 1). Hybridization was performed with a final wash in0.3×SSC, 0.3% SDS at 62° C. Sequencing was performed on both strandswith an ABI Prism sequencer (Perkin-Elmer) according to themanufacturer's instructions. Alignments were generated with the Gap andLineup programs of the Wisconsin Package of UNIX sequence softwareprograms (Oxford Molecular Group).

[0039] Results:

[0040] To obtain cDNAs encoding PDE4B isoforms, a rat cortex cDNAlibrary was screened with a probe corresponding to UCR1 and UCR2 of ratPDE4B3 (Huston et al., Biochem. J. 328:549-56 (1997)). This probe wasdesigned to detect all “long” (i.e., UCR1-containing) PDE4B isoforms.cDNAs encoding two different PDE4B isoforms were detected in the screen(see FIG. 1). One cDNA clone, called pRPDE89 (SEQ ID NO: 5), encoded aprotein of 736 amino acids (SEQ ID NO: 6). This isoform was identical inlength and had greater than 96% amino acid identity (712/736 amino acidsidentical, FIG. 2) with the human PDE4B1 isoform (SEQ ID NO: 7). Bolgeret al., Mol. Cell Biol. 13:6558-71 (1993). It was therefore concludedthat pRPDE89 encodes the rat PDE4B1 isoform.

[0041] Also detected in the screen was a cDNA clone, called pRPDE90 (SEQID NO: 1), which encoded the complete open reading frame of a novelPDE4B isoform. This new isoform was called PDE4B4, using the acceptednomenclature. Beavo, Physiol. Rev. 75:725-48 (1995). The PDE4B4 proteinconsists of 659 amino acids (SEQ ID NO: 2), 17 of which are located atthe extreme amino-terminal end of the protein and show no detectablehomology to any previously cloned PDE4B sequence (SEQ ID NOS: 3, 4). Theremaining 642 amino acids are identical to the corresponding regions ofthe “long” PDE4B isoforms PDE4B1 and PDE4B3 (FIG. 3). The nucleotidesequences of the common regions of PDE4B1, PDE4B3 and PDE4B4 are alsoidentical. The sequence of the novel region of PDE4B4 was confirmed bythe sequence of another clone isolated in the screen, called pRPDE92(SEQ ID NO: 10), which completely overlapped the novel region of pRPDE90and contained sequence of an additional portion of the 5′ untranslatedregion of the mRNA.

[0042] The invention may be embodied in other specific forms withoutdeparting from its essential characteristics. The described embodimentsare to be considered in all respects only as illustrative and notrestrictive. The scope of the invention is, therefore, indicated by theappended claims rather than by the foregoing description. All changesthat come within the meaning and range of equivalency of the claims areto be embraced within their scope.

1 11 1 2433 DNA Rattus norvegicus CDS (262)..(2238) 1 gaattcggcacgagcaattt cctcatctga tttctaaagg aagctacttg cgatggtcct 60 ctgcaacctcgtgtgtcgat tgctaagtca ttgctactcg cattggaatg atctctaccc 120 cgcaatggagagtggcatgc catcagaaag aaaaacgaac ggacaaagag ctcagtagaa 180 actctggcagcgagaacaca gagaaacgca tggagatgag ctaagtcgct gagcggtggg 240 ctgacagtgtaccggttcag g atg ttg cac gtg aac gac ttg cct cct ccc 291 Met Leu His ValAsn Asp Leu Pro Pro Pro 1 5 10 agg cga cac tcg tgg ata tgc ttt gat gtggaa aat ggc cct tct cca 339 Arg Arg His Ser Trp Ile Cys Phe Asp Val GluAsn Gly Pro Ser Pro 15 20 25 ggt cgg agc cca ctg gac cct caa gcc agc tcttct tca gga ctg gta 387 Gly Arg Ser Pro Leu Asp Pro Gln Ala Ser Ser SerSer Gly Leu Val 30 35 40 ctt cat gcc gcc ttc cct ggg cac agc caa cgc agagag tct ttt ctc 435 Leu His Ala Ala Phe Pro Gly His Ser Gln Arg Arg GluSer Phe Leu 45 50 55 tac aga tcc gac agc gac tat gac ttg tca cca aaa gcgatg tca agg 483 Tyr Arg Ser Asp Ser Asp Tyr Asp Leu Ser Pro Lys Ala MetSer Arg 60 65 70 aac tcc tca ctt ccc agc gaa caa cac ggc gat gac ctg attgtc act 531 Asn Ser Ser Leu Pro Ser Glu Gln His Gly Asp Asp Leu Ile ValThr 75 80 85 90 cct ttt gcc cag gtt ctt gcc agc ttg cga agc gta aga aacaat ttc 579 Pro Phe Ala Gln Val Leu Ala Ser Leu Arg Ser Val Arg Asn AsnPhe 95 100 105 acc ctg ctg aca aac ctt cac gga gca ccg aac aag agg tcgcca gcg 627 Thr Leu Leu Thr Asn Leu His Gly Ala Pro Asn Lys Arg Ser ProAla 110 115 120 gct agt cag gct cca gtc acc aga gtc agc ctg caa gaa gaatca tat 675 Ala Ser Gln Ala Pro Val Thr Arg Val Ser Leu Gln Glu Glu SerTyr 125 130 135 cag aaa cta gca atg gag acg ctg gag gaa cta gac tgg tgccta gac 723 Gln Lys Leu Ala Met Glu Thr Leu Glu Glu Leu Asp Trp Cys LeuAsp 140 145 150 cag cta gag acc atc cag acc tac cgc tct gtc agc gag atggct tca 771 Gln Leu Glu Thr Ile Gln Thr Tyr Arg Ser Val Ser Glu Met AlaSer 155 160 165 170 aac aag ttc aaa agg atg ctg aac cgg gag ctg aca cacctc tca gag 819 Asn Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His LeuSer Glu 175 180 185 atg agc aga tca ggg aac caa gtg tct gaa tac att tcgaac acg ttc 867 Met Ser Arg Ser Gly Asn Gln Val Ser Glu Tyr Ile Ser AsnThr Phe 190 195 200 tta gac aag cag aac gat gtg gaa atc cca tct ccc acccag aag gac 915 Leu Asp Lys Gln Asn Asp Val Glu Ile Pro Ser Pro Thr GlnLys Asp 205 210 215 agg gag aag aag aag aag cag cag ctc atg acc cag ataagt gga gtg 963 Arg Glu Lys Lys Lys Lys Gln Gln Leu Met Thr Gln Ile SerGly Val 220 225 230 aag aaa ctg atg cac agc tca agc ctg aac aac aca agcatc tca cgc 1011 Lys Lys Leu Met His Ser Ser Ser Leu Asn Asn Thr Ser IleSer Arg 235 240 245 250 ttt gga gtc aac acg gaa aat gag gat cat cta gccaag gag ctg gaa 1059 Phe Gly Val Asn Thr Glu Asn Glu Asp His Leu Ala LysGlu Leu Glu 255 260 265 gac ctg aac aaa tgg ggc ctt aac atc ttc aac gtggct ggg tac tcc 1107 Asp Leu Asn Lys Trp Gly Leu Asn Ile Phe Asn Val AlaGly Tyr Ser 270 275 280 cat aat cgg ccc ctc aca tgc atc atg tac gcc attttc cag gaa aga 1155 His Asn Arg Pro Leu Thr Cys Ile Met Tyr Ala Ile PheGln Glu Arg 285 290 295 gac ctt cta aag acg ttt aaa atc tcc tcc gac accttc gta acc tac 1203 Asp Leu Leu Lys Thr Phe Lys Ile Ser Ser Asp Thr PheVal Thr Tyr 300 305 310 atg atg act tta gaa gac cat tac cat tct gat gtggcg tat cac aac 1251 Met Met Thr Leu Glu Asp His Tyr His Ser Asp Val AlaTyr His Asn 315 320 325 330 agc ctg cac gct gct gac gtg gcc cag tca acgcac gtt ctc ctc tct 1299 Ser Leu His Ala Ala Asp Val Ala Gln Ser Thr HisVal Leu Leu Ser 335 340 345 acg cca gca ctg gat gct gtc ttc aca gac ctggaa atc ctg gct gcc 1347 Thr Pro Ala Leu Asp Ala Val Phe Thr Asp Leu GluIle Leu Ala Ala 350 355 360 att ttt gca gct gcc atc cat gat gtt gat catcct gga gtc tcc aat 1395 Ile Phe Ala Ala Ala Ile His Asp Val Asp His ProGly Val Ser Asn 365 370 375 cag ttt ctc atc aat aca aat tcc gaa ctt gctttg atg tat aat gac 1443 Gln Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala LeuMet Tyr Asn Asp 380 385 390 gaa tct gtg ctg gaa aac cat cac ctc gct gtggga ttc aag ctc ctt 1491 Glu Ser Val Leu Glu Asn His His Leu Ala Val GlyPhe Lys Leu Leu 395 400 405 410 caa gag gaa cat tgc gac atc ttt cag aatctt acc aag aag caa cgc 1539 Gln Glu Glu His Cys Asp Ile Phe Gln Asn LeuThr Lys Lys Gln Arg 415 420 425 cag aca ctc agg aaa atg gtg att gac atggtg tta gca act gat atg 1587 Gln Thr Leu Arg Lys Met Val Ile Asp Met ValLeu Ala Thr Asp Met 430 435 440 tcc aag cac atg agc ctc ctg gct gac cttaaa acg atg gta gaa acc 1635 Ser Lys His Met Ser Leu Leu Ala Asp Leu LysThr Met Val Glu Thr 445 450 455 aaa aag gtg acg agc tcc ggt gtt ctc ctcctg gac aac tat act gac 1683 Lys Lys Val Thr Ser Ser Gly Val Leu Leu LeuAsp Asn Tyr Thr Asp 460 465 470 cgg ata cag gtt ctt cgc aac atg gta cattgt gca gac ctg agc aac 1731 Arg Ile Gln Val Leu Arg Asn Met Val His CysAla Asp Leu Ser Asn 475 480 485 490 cct acc aag tcc ttg gag ttg tat cggcaa tgg act gat cgc atc atg 1779 Pro Thr Lys Ser Leu Glu Leu Tyr Arg GlnTrp Thr Asp Arg Ile Met 495 500 505 gag gag ttt ttc caa cag gga gac aaagaa cgg gag agg gga atg gag 1827 Glu Glu Phe Phe Gln Gln Gly Asp Lys GluArg Glu Arg Gly Met Glu 510 515 520 att agc cca atg tgt gat aaa cac acagct tct gtg gaa aag tcc cag 1875 Ile Ser Pro Met Cys Asp Lys His Thr AlaSer Val Glu Lys Ser Gln 525 530 535 gtt ggt ttc att gac tac att gtc catcca ttg tgg gag acc tgg gca 1923 Val Gly Phe Ile Asp Tyr Ile Val His ProLeu Trp Glu Thr Trp Ala 540 545 550 gac ctg gtt cag cct gat gct caa gacatt ttg gac aca cta gaa gat 1971 Asp Leu Val Gln Pro Asp Ala Gln Asp IleLeu Asp Thr Leu Glu Asp 555 560 565 570 aac agg aac tgg tac cag agt atgatt ccc cag agc ccc tct cca cca 2019 Asn Arg Asn Trp Tyr Gln Ser Met IlePro Gln Ser Pro Ser Pro Pro 575 580 585 ctg gac gag agg agc agg gac tgccaa ggc ctt atg gag aag ttt cag 2067 Leu Asp Glu Arg Ser Arg Asp Cys GlnGly Leu Met Glu Lys Phe Gln 590 595 600 ttc gaa ctg acc ctt gaa gaa gaggat tct gaa gga ccg gaa aag gag 2115 Phe Glu Leu Thr Leu Glu Glu Glu AspSer Glu Gly Pro Glu Lys Glu 605 610 615 gga gaa ggc ccc aac tat ttc agcagc aca aag aca ctt tgt gtg atc 2163 Gly Glu Gly Pro Asn Tyr Phe Ser SerThr Lys Thr Leu Cys Val Ile 620 625 630 gat cca gag aac agg gat tct ctggaa gag act gac ata gac att gcc 2211 Asp Pro Glu Asn Arg Asp Ser Leu GluGlu Thr Asp Ile Asp Ile Ala 635 640 645 650 aca gaa gac aag tct ctg atcgac aca taatctccct ctgtgtggag 2258 Thr Glu Asp Lys Ser Leu Ile Asp Thr655 gtgaacattc tatccttgac gagcatgcca gctgagtggt agggcccacc taccagagcc2318 aaggcctgca caaaacaaag gccacctggc tttgcagtta cttgagtttg gagccagaat2378 gcaaggccgt gaagcaaata gcagttccgt gctgccttgc cttgccggcg agctt 2433 2659 PRT Rattus norvegicus 2 Met Leu His Val Asn Asp Leu Pro Pro Pro ArgArg His Ser Trp Ile 1 5 10 15 Cys Phe Asp Val Glu Asn Gly Pro Ser ProGly Arg Ser Pro Leu Asp 20 25 30 Pro Gln Ala Ser Ser Ser Ser Gly Leu ValLeu His Ala Ala Phe Pro 35 40 45 Gly His Ser Gln Arg Arg Glu Ser Phe LeuTyr Arg Ser Asp Ser Asp 50 55 60 Tyr Asp Leu Ser Pro Lys Ala Met Ser ArgAsn Ser Ser Leu Pro Ser 65 70 75 80 Glu Gln His Gly Asp Asp Leu Ile ValThr Pro Phe Ala Gln Val Leu 85 90 95 Ala Ser Leu Arg Ser Val Arg Asn AsnPhe Thr Leu Leu Thr Asn Leu 100 105 110 His Gly Ala Pro Asn Lys Arg SerPro Ala Ala Ser Gln Ala Pro Val 115 120 125 Thr Arg Val Ser Leu Gln GluGlu Ser Tyr Gln Lys Leu Ala Met Glu 130 135 140 Thr Leu Glu Glu Leu AspTrp Cys Leu Asp Gln Leu Glu Thr Ile Gln 145 150 155 160 Thr Tyr Arg SerVal Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met 165 170 175 Leu Asn ArgGlu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn 180 185 190 Gln ValSer Glu Tyr Ile Ser Asn Thr Phe Leu Asp Lys Gln Asn Asp 195 200 205 ValGlu Ile Pro Ser Pro Thr Gln Lys Asp Arg Glu Lys Lys Lys Lys 210 215 220Gln Gln Leu Met Thr Gln Ile Ser Gly Val Lys Lys Leu Met His Ser 225 230235 240 Ser Ser Leu Asn Asn Thr Ser Ile Ser Arg Phe Gly Val Asn Thr Glu245 250 255 Asn Glu Asp His Leu Ala Lys Glu Leu Glu Asp Leu Asn Lys TrpGly 260 265 270 Leu Asn Ile Phe Asn Val Ala Gly Tyr Ser His Asn Arg ProLeu Thr 275 280 285 Cys Ile Met Tyr Ala Ile Phe Gln Glu Arg Asp Leu LeuLys Thr Phe 290 295 300 Lys Ile Ser Ser Asp Thr Phe Val Thr Tyr Met MetThr Leu Glu Asp 305 310 315 320 His Tyr His Ser Asp Val Ala Tyr His AsnSer Leu His Ala Ala Asp 325 330 335 Val Ala Gln Ser Thr His Val Leu LeuSer Thr Pro Ala Leu Asp Ala 340 345 350 Val Phe Thr Asp Leu Glu Ile LeuAla Ala Ile Phe Ala Ala Ala Ile 355 360 365 His Asp Val Asp His Pro GlyVal Ser Asn Gln Phe Leu Ile Asn Thr 370 375 380 Asn Ser Glu Leu Ala LeuMet Tyr Asn Asp Glu Ser Val Leu Glu Asn 385 390 395 400 His His Leu AlaVal Gly Phe Lys Leu Leu Gln Glu Glu His Cys Asp 405 410 415 Ile Phe GlnAsn Leu Thr Lys Lys Gln Arg Gln Thr Leu Arg Lys Met 420 425 430 Val IleAsp Met Val Leu Ala Thr Asp Met Ser Lys His Met Ser Leu 435 440 445 LeuAla Asp Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr Ser Ser 450 455 460Gly Val Leu Leu Leu Asp Asn Tyr Thr Asp Arg Ile Gln Val Leu Arg 465 470475 480 Asn Met Val His Cys Ala Asp Leu Ser Asn Pro Thr Lys Ser Leu Glu485 490 495 Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu Glu Phe Phe GlnGln 500 505 510 Gly Asp Lys Glu Arg Glu Arg Gly Met Glu Ile Ser Pro MetCys Asp 515 520 525 Lys His Thr Ala Ser Val Glu Lys Ser Gln Val Gly PheIle Asp Tyr 530 535 540 Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp LeuVal Gln Pro Asp 545 550 555 560 Ala Gln Asp Ile Leu Asp Thr Leu Glu AspAsn Arg Asn Trp Tyr Gln 565 570 575 Ser Met Ile Pro Gln Ser Pro Ser ProPro Leu Asp Glu Arg Ser Arg 580 585 590 Asp Cys Gln Gly Leu Met Glu LysPhe Gln Phe Glu Leu Thr Leu Glu 595 600 605 Glu Glu Asp Ser Glu Gly ProGlu Lys Glu Gly Glu Gly Pro Asn Tyr 610 615 620 Phe Ser Ser Thr Lys ThrLeu Cys Val Ile Asp Pro Glu Asn Arg Asp 625 630 635 640 Ser Leu Glu GluThr Asp Ile Asp Ile Ala Thr Glu Asp Lys Ser Leu 645 650 655 Ile Asp Thr3 51 DNA Rattus norvegicus CDS (1)..(51) 3 atg ttg cac gtg aac gac ttgcct cct ccc agg cga cac tcg tgg ata 48 Met Leu His Val Asn Asp Leu ProPro Pro Arg Arg His Ser Trp Ile 1 5 10 15 tgc 51 Cys 4 17 PRT Rattusnorvegicus 4 Met Leu His Val Asn Asp Leu Pro Pro Pro Arg Arg His Ser TrpIle 1 5 10 15 Cys 5 3022 DNA Rattus norvegicus CDS (325)..(2532) 5gaattcggca cgaggcgcgg gggcgggggc ggcgtgtagt ggcagacggc cgcagggatt 60atgaatgggg gtgggggccg gcgagttgag gttccacccg ggatcgtccg caccggctga 120tgggcacgca gggctgcgtg taatcctcca gcctcggtgg agggaggctg cagcgagcgc 180cggctggcag taagggttct tctgcaaaag tcccctgcgg ttgcgcgcgt ggagtgccgg 240ggagctcggc caggtctagt ctgcagtcag caaagctgca gcaaacagca gacatctcca 300gaggagctgt ttgccacatc tata atg aag aaa agt agg agt gtg atg gcc 351 MetLys Lys Ser Arg Ser Val Met Ala 1 5 gtg act gca gat gat aat ctt aag gactat ttt gaa tgt agc ttg agt 399 Val Thr Ala Asp Asp Asn Leu Lys Asp TyrPhe Glu Cys Ser Leu Ser 10 15 20 25 aaa tcc tac agt tct tcc agt tat accctt ggg att gac ctc tgg aga 447 Lys Ser Tyr Ser Ser Ser Ser Tyr Thr LeuGly Ile Asp Leu Trp Arg 30 35 40 ggc aga agg tgc tgt tca gga aac tta cagttg cca cca ttg tcc cag 495 Gly Arg Arg Cys Cys Ser Gly Asn Leu Gln LeuPro Pro Leu Ser Gln 45 50 55 aga caa agt gaa agg gca agg aca cct gag ggagat ggc att tcc agg 543 Arg Gln Ser Glu Arg Ala Arg Thr Pro Glu Gly AspGly Ile Ser Arg 60 65 70 cca acc acg cta cct ttg acg aca ctt ccc agc attgct ata aca act 591 Pro Thr Thr Leu Pro Leu Thr Thr Leu Pro Ser Ile AlaIle Thr Thr 75 80 85 gta agc cag gag tgc ttt gat gtg gaa aat ggc cct tctcca ggt cgg 639 Val Ser Gln Glu Cys Phe Asp Val Glu Asn Gly Pro Ser ProGly Arg 90 95 100 105 agc cca ctg gac cct caa gcc agc tct tct tca ggactg gta ctt cat 687 Ser Pro Leu Asp Pro Gln Ala Ser Ser Ser Ser Gly LeuVal Leu His 110 115 120 gcc gcc ttc cct ggg cac agc caa cgc aga gag tctttt ctc tac aga 735 Ala Ala Phe Pro Gly His Ser Gln Arg Arg Glu Ser PheLeu Tyr Arg 125 130 135 tcc gac agc gac tat gac ttg tca cca aaa gcg atgtca agg aac tcc 783 Ser Asp Ser Asp Tyr Asp Leu Ser Pro Lys Ala Met SerArg Asn Ser 140 145 150 tca ctt ccc agc gaa caa cac ggc gat gac ctg attgtc act cct ttt 831 Ser Leu Pro Ser Glu Gln His Gly Asp Asp Leu Ile ValThr Pro Phe 155 160 165 gcc cag gtt ctt gcc agc ttg cga agc gta aga aacaat ttc acc ctg 879 Ala Gln Val Leu Ala Ser Leu Arg Ser Val Arg Asn AsnPhe Thr Leu 170 175 180 185 ctg aca aac ctt cac gga gca ccg aac aag aggtcg cca gcg gct agt 927 Leu Thr Asn Leu His Gly Ala Pro Asn Lys Arg SerPro Ala Ala Ser 190 195 200 cag gct cca gtc acc aga gtc agc ctg caa gaagaa tca tat cag aaa 975 Gln Ala Pro Val Thr Arg Val Ser Leu Gln Glu GluSer Tyr Gln Lys 205 210 215 cta gca atg gag acg ctg gag gaa cta gac tggtgc cta gac cag cta 1023 Leu Ala Met Glu Thr Leu Glu Glu Leu Asp Trp CysLeu Asp Gln Leu 220 225 230 gag acc atc cag acc tac cgc tct gtc agc gagatg gct tca aac aag 1071 Glu Thr Ile Gln Thr Tyr Arg Ser Val Ser Glu MetAla Ser Asn Lys 235 240 245 ttc aaa agg atg ctg aac cgg gag ctg aca cacctc tca gag atg agc 1119 Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His LeuSer Glu Met Ser 250 255 260 265 aga tca ggg aac caa gtg tct gaa tac atttcg aac acg ttc tta gac 1167 Arg Ser Gly Asn Gln Val Ser Glu Tyr Ile SerAsn Thr Phe Leu Asp 270 275 280 aag cag aac gat gtg gaa atc cca tct cccacc cag aag gac agg gag 1215 Lys Gln Asn Asp Val Glu Ile Pro Ser Pro ThrGln Lys Asp Arg Glu 285 290 295 aag aag aag aag cag cag ctc atg acc cagata agt gga gtg aag aaa 1263 Lys Lys Lys Lys Gln Gln Leu Met Thr Gln IleSer Gly Val Lys Lys 300 305 310 ctg atg cac agc tca agc ctg aac aac acaagc atc tca cgc ttt gga 1311 Leu Met His Ser Ser Ser Leu Asn Asn Thr SerIle Ser Arg Phe Gly 315 320 325 gtc aac acg gaa aat gag gat cat cta gccaag gag ctg gaa gac ctg 1359 Val Asn Thr Glu Asn Glu Asp His Leu Ala LysGlu Leu Glu Asp Leu 330 335 340 345 aac aaa tgg ggc ctt aac atc ttc aacgtg gct ggg tac tcc cat aat 1407 Asn Lys Trp Gly Leu Asn Ile Phe Asn ValAla Gly Tyr Ser His Asn 350 355 360 cgg ccc ctc aca tgc atc atg tac gccatt ttc cag gaa aga gac ctt 1455 Arg Pro Leu Thr Cys Ile Met Tyr Ala IlePhe Gln Glu Arg Asp Leu 365 370 375 cta aag acg ttt aaa atc tcc tcc gacacc ttc gta acc tac atg atg 1503 Leu Lys Thr Phe Lys Ile Ser Ser Asp ThrPhe Val Thr Tyr Met Met 380 385 390 act tta gaa gac cat tac cat tct gatgtg gcg tat cac aac agc ctg 1551 Thr Leu Glu Asp His Tyr His Ser Asp ValAla Tyr His Asn Ser Leu 395 400 405 cac gct gct gac gtg gcc cag tca acgcac gtt ctc ctc tct acg cca 1599 His Ala Ala Asp Val Ala Gln Ser Thr HisVal Leu Leu Ser Thr Pro 410 415 420 425 gca ctg gat gct gtc ttc aca gacctg gaa atc ctg gct gcc att ttt 1647 Ala Leu Asp Ala Val Phe Thr Asp LeuGlu Ile Leu Ala Ala Ile Phe 430 435 440 gca gct gcc atc cat gat gtt gatcat cct gga gtc tcc aat cag ttt 1695 Ala Ala Ala Ile His Asp Val Asp HisPro Gly Val Ser Asn Gln Phe 445 450 455 ctc atc aat aca aat tcc gaa cttgct ttg atg tat aat gac gaa tct 1743 Leu Ile Asn Thr Asn Ser Glu Leu AlaLeu Met Tyr Asn Asp Glu Ser 460 465 470 gtg ctg gaa aac cat cac ctc gctgtg gga ttc aag ctc ctt caa gag 1791 Val Leu Glu Asn His His Leu Ala ValGly Phe Lys Leu Leu Gln Glu 475 480 485 gaa cat tgc gac atc ttt cag aatctt acc aag aag caa cgc cag aca 1839 Glu His Cys Asp Ile Phe Gln Asn LeuThr Lys Lys Gln Arg Gln Thr 490 495 500 505 ctc agg aaa atg gtg att gacatg gtg tta gca act gat atg tcc aag 1887 Leu Arg Lys Met Val Ile Asp MetVal Leu Ala Thr Asp Met Ser Lys 510 515 520 cac atg agc ctc ctg gct gacctt aaa acg atg gta gaa acc aaa aag 1935 His Met Ser Leu Leu Ala Asp LeuLys Thr Met Val Glu Thr Lys Lys 525 530 535 gtg acg agc tcc ggt gtt ctcctc ctg gac aac tat act gac cgg ata 1983 Val Thr Ser Ser Gly Val Leu LeuLeu Asp Asn Tyr Thr Asp Arg Ile 540 545 550 cag gtt ctt cgc aac atg gtacat tgt gca gac ctg agc aac cct acc 2031 Gln Val Leu Arg Asn Met Val HisCys Ala Asp Leu Ser Asn Pro Thr 555 560 565 aag tcc ttg gag ttg tat cggcaa tgg act gat cgc atc atg gag gag 2079 Lys Ser Leu Glu Leu Tyr Arg GlnTrp Thr Asp Arg Ile Met Glu Glu 570 575 580 585 ttt ttc caa cag gga gacaaa gaa cgg gag agg gga atg gag att agc 2127 Phe Phe Gln Gln Gly Asp LysGlu Arg Glu Arg Gly Met Glu Ile Ser 590 595 600 cca atg tgt gat aaa cacaca gct tct gtg gaa aag tcc cag gtt ggt 2175 Pro Met Cys Asp Lys His ThrAla Ser Val Glu Lys Ser Gln Val Gly 605 610 615 ttc att gac tac att gtccat cca ttg tgg gag acc tgg gca gac ctg 2223 Phe Ile Asp Tyr Ile Val HisPro Leu Trp Glu Thr Trp Ala Asp Leu 620 625 630 gtt cag cct gat gct caagac att ttg gac aca cta gaa gat aac agg 2271 Val Gln Pro Asp Ala Gln AspIle Leu Asp Thr Leu Glu Asp Asn Arg 635 640 645 aac tgg tac cag agt atgatt ccc cag agc ccc tct cca cca ctg gac 2319 Asn Trp Tyr Gln Ser Met IlePro Gln Ser Pro Ser Pro Pro Leu Asp 650 655 660 665 gag agg agc agg gactgc caa ggc ctt atg gag aag ttt cag ttc gaa 2367 Glu Arg Ser Arg Asp CysGln Gly Leu Met Glu Lys Phe Gln Phe Glu 670 675 680 ctg acc ctt gaa gaagag gat tct gaa gga ccg gaa aag gag gga gaa 2415 Leu Thr Leu Glu Glu GluAsp Ser Glu Gly Pro Glu Lys Glu Gly Glu 685 690 695 ggc ccc aac tat ttcagc agc aca aag aca ctt tgt gtg atc gat cca 2463 Gly Pro Asn Tyr Phe SerSer Thr Lys Thr Leu Cys Val Ile Asp Pro 700 705 710 gag aac agg gat tctctg gaa gag act gac ata gac att gcc aca gaa 2511 Glu Asn Arg Asp Ser LeuGlu Glu Thr Asp Ile Asp Ile Ala Thr Glu 715 720 725 gac aag tct ctg atcgac aca taatctccct ctgtgtggag gtgaacattc 2562 Asp Lys Ser Leu Ile AspThr 730 735 tatccttgac gagcatgcca gctgagtggt agggcccacc taccagagccaaggcctgca 2622 caaaacaaag gccacctggc ctttgcagtt acttgagttt ggagccagaatgcaaggccg 2682 tgaagcaaat agcagttccg tgctgccttg ccttgccggc gagcttggcggagacccgca 2742 gctgtagtag aagccagttc ccagcacagc taaatggctt gaaaacagaggacagaaagc 2802 tgagagattg ctctgcaata ggtgttgagg ggctgtcccg acaggtgactgaactcacta 2862 acaacttcat ctataaatct cacccatcct gttgtctgcc aacctgtgtgccttttttgt 2922 aaaatgtttt cgtgtctttg aaatgcctgt tgaatatcta gagtttagtacctccttcta 2982 caaacttttt tgagtctttc tgggaaaaaa aaacctgcag 3022 6 736PRT Rattus norvegicus 6 Met Lys Lys Ser Arg Ser Val Met Ala Val Thr AlaAsp Asp Asn Leu 1 5 10 15 Lys Asp Tyr Phe Glu Cys Ser Leu Ser Lys SerTyr Ser Ser Ser Ser 20 25 30 Tyr Thr Leu Gly Ile Asp Leu Trp Arg Gly ArgArg Cys Cys Ser Gly 35 40 45 Asn Leu Gln Leu Pro Pro Leu Ser Gln Arg GlnSer Glu Arg Ala Arg 50 55 60 Thr Pro Glu Gly Asp Gly Ile Ser Arg Pro ThrThr Leu Pro Leu Thr 65 70 75 80 Thr Leu Pro Ser Ile Ala Ile Thr Thr ValSer Gln Glu Cys Phe Asp 85 90 95 Val Glu Asn Gly Pro Ser Pro Gly Arg SerPro Leu Asp Pro Gln Ala 100 105 110 Ser Ser Ser Ser Gly Leu Val Leu HisAla Ala Phe Pro Gly His Ser 115 120 125 Gln Arg Arg Glu Ser Phe Leu TyrArg Ser Asp Ser Asp Tyr Asp Leu 130 135 140 Ser Pro Lys Ala Met Ser ArgAsn Ser Ser Leu Pro Ser Glu Gln His 145 150 155 160 Gly Asp Asp Leu IleVal Thr Pro Phe Ala Gln Val Leu Ala Ser Leu 165 170 175 Arg Ser Val ArgAsn Asn Phe Thr Leu Leu Thr Asn Leu His Gly Ala 180 185 190 Pro Asn LysArg Ser Pro Ala Ala Ser Gln Ala Pro Val Thr Arg Val 195 200 205 Ser LeuGln Glu Glu Ser Tyr Gln Lys Leu Ala Met Glu Thr Leu Glu 210 215 220 GluLeu Asp Trp Cys Leu Asp Gln Leu Glu Thr Ile Gln Thr Tyr Arg 225 230 235240 Ser Val Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu Asn Arg 245250 255 Glu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln Val Ser260 265 270 Glu Tyr Ile Ser Asn Thr Phe Leu Asp Lys Gln Asn Asp Val GluIle 275 280 285 Pro Ser Pro Thr Gln Lys Asp Arg Glu Lys Lys Lys Lys GlnGln Leu 290 295 300 Met Thr Gln Ile Ser Gly Val Lys Lys Leu Met His SerSer Ser Leu 305 310 315 320 Asn Asn Thr Ser Ile Ser Arg Phe Gly Val AsnThr Glu Asn Glu Asp 325 330 335 His Leu Ala Lys Glu Leu Glu Asp Leu AsnLys Trp Gly Leu Asn Ile 340 345 350 Phe Asn Val Ala Gly Tyr Ser His AsnArg Pro Leu Thr Cys Ile Met 355 360 365 Tyr Ala Ile Phe Gln Glu Arg AspLeu Leu Lys Thr Phe Lys Ile Ser 370 375 380 Ser Asp Thr Phe Val Thr TyrMet Met Thr Leu Glu Asp His Tyr His 385 390 395 400 Ser Asp Val Ala TyrHis Asn Ser Leu His Ala Ala Asp Val Ala Gln 405 410 415 Ser Thr His ValLeu Leu Ser Thr Pro Ala Leu Asp Ala Val Phe Thr 420 425 430 Asp Leu GluIle Leu Ala Ala Ile Phe Ala Ala Ala Ile His Asp Val 435 440 445 Asp HisPro Gly Val Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu 450 455 460 LeuAla Leu Met Tyr Asn Asp Glu Ser Val Leu Glu Asn His His Leu 465 470 475480 Ala Val Gly Phe Lys Leu Leu Gln Glu Glu His Cys Asp Ile Phe Gln 485490 495 Asn Leu Thr Lys Lys Gln Arg Gln Thr Leu Arg Lys Met Val Ile Asp500 505 510 Met Val Leu Ala Thr Asp Met Ser Lys His Met Ser Leu Leu AlaAsp 515 520 525 Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr Ser Ser GlyVal Leu 530 535 540 Leu Leu Asp Asn Tyr Thr Asp Arg Ile Gln Val Leu ArgAsn Met Val 545 550 555 560 His Cys Ala Asp Leu Ser Asn Pro Thr Lys SerLeu Glu Leu Tyr Arg 565 570 575 Gln Trp Thr Asp Arg Ile Met Glu Glu PhePhe Gln Gln Gly Asp Lys 580 585 590 Glu Arg Glu Arg Gly Met Glu Ile SerPro Met Cys Asp Lys His Thr 595 600 605 Ala Ser Val Glu Lys Ser Gln ValGly Phe Ile Asp Tyr Ile Val His 610 615 620 Pro Leu Trp Glu Thr Trp AlaAsp Leu Val Gln Pro Asp Ala Gln Asp 625 630 635 640 Ile Leu Asp Thr LeuGlu Asp Asn Arg Asn Trp Tyr Gln Ser Met Ile 645 650 655 Pro Gln Ser ProSer Pro Pro Leu Asp Glu Arg Ser Arg Asp Cys Gln 660 665 670 Gly Leu MetGlu Lys Phe Gln Phe Glu Leu Thr Leu Glu Glu Glu Asp 675 680 685 Ser GluGly Pro Glu Lys Glu Gly Glu Gly Pro Asn Tyr Phe Ser Ser 690 695 700 ThrLys Thr Leu Cys Val Ile Asp Pro Glu Asn Arg Asp Ser Leu Glu 705 710 715720 Glu Thr Asp Ile Asp Ile Ala Thr Glu Asp Lys Ser Leu Ile Asp Thr 725730 735 7 736 PRT Homo sapiens 7 Met Lys Lys Ser Arg Ser Val Met Ala ValThr Ala Asp Asp Asn Leu 1 5 10 15 Lys Asp Tyr Phe Glu Cys Ser Leu SerLys Ser Tyr Ser Ser Ser Ser 20 25 30 Tyr Thr Leu Gly Ile Asp Leu Trp ArgGly Arg Arg Cys Cys Ser Gly 35 40 45 Asn Leu Gln Leu Pro Pro Leu Ser GlnArg Gln Ser Glu Arg Ala Arg 50 55 60 Thr Pro Glu Gly Asp Gly Ile Ser ArgPro Thr Thr Leu Pro Leu Thr 65 70 75 80 Thr Leu Pro Ser Ile Ala Ile ThrThr Val Ser Gln Glu Cys Phe Asp 85 90 95 Val Glu Asn Gly Pro Ser Pro GlyArg Ser Pro Leu Asp Pro Gln Ala 100 105 110 Ser Ser Ser Ser Gly Leu ValLeu His Ala Ala Phe Pro Gly His Ser 115 120 125 Gln Arg Arg Glu Ser PheLeu Tyr Arg Ser Asp Ser Asp Tyr Asp Leu 130 135 140 Ser Pro Lys Ala MetSer Arg Asn Ser Ser Leu Pro Ser Glu Gln His 145 150 155 160 Gly Asp AspLeu Ile Val Thr Pro Phe Ala Gln Val Leu Ala Ser Leu 165 170 175 Arg SerVal Arg Asn Asn Phe Thr Leu Leu Thr Asn Leu His Gly Ala 180 185 190 ProAsn Lys Arg Ser Pro Ala Ala Ser Gln Ala Pro Val Thr Arg Val 195 200 205Ser Leu Gln Glu Glu Ser Tyr Gln Lys Leu Ala Met Glu Thr Leu Glu 210 215220 Glu Leu Asp Trp Cys Leu Asp Gln Leu Glu Thr Ile Gln Thr Tyr Arg 225230 235 240 Ser Val Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu AsnArg 245 250 255 Glu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn GlnVal Ser 260 265 270 Glu Tyr Ile Ser Asn Thr Phe Leu Asp Lys Gln Asn AspVal Glu Ile 275 280 285 Pro Ser Pro Thr Gln Lys Asp Arg Glu Lys Lys LysLys Gln Gln Leu 290 295 300 Met Thr Gln Ile Ser Gly Val Lys Lys Leu MetHis Ser Ser Ser Leu 305 310 315 320 Asn Asn Thr Ser Ile Ser Arg Phe GlyVal Asn Thr Glu Asn Glu Asp 325 330 335 His Leu Ala Lys Glu Leu Glu AspLeu Asn Lys Trp Gly Leu Asn Ile 340 345 350 Phe Asn Val Ala Gly Tyr SerHis Asn Arg Pro Leu Thr Cys Ile Met 355 360 365 Tyr Ala Ile Phe Gln GluArg Asp Leu Leu Lys Thr Phe Lys Ile Ser 370 375 380 Ser Asp Thr Phe ValThr Tyr Met Met Thr Leu Glu Asp His Tyr His 385 390 395 400 Ser Asp ValAla Tyr His Asn Ser Leu His Ala Ala Asp Val Ala Gln 405 410 415 Ser ThrHis Val Leu Leu Ser Thr Pro Ala Leu Asp Ala Val Phe Thr 420 425 430 AspLeu Glu Ile Leu Ala Ala Ile Phe Ala Ala Ala Ile His Asp Val 435 440 445Asp His Pro Gly Val Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu 450 455460 Leu Ala Leu Met Tyr Asn Asp Glu Ser Val Leu Glu Asn His His Leu 465470 475 480 Ala Val Gly Phe Lys Leu Leu Gln Glu Glu His Cys Asp Ile PheGln 485 490 495 Asn Leu Thr Lys Lys Gln Arg Gln Thr Leu Arg Lys Met ValIle Asp 500 505 510 Met Val Leu Ala Thr Asp Met Ser Lys His Met Ser LeuLeu Ala Asp 515 520 525 Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr SerSer Gly Val Leu 530 535 540 Leu Leu Asp Asn Tyr Thr Asp Arg Ile Gln ValLeu Arg Asn Met Val 545 550 555 560 His Cys Ala Asp Leu Ser Asn Pro ThrLys Ser Leu Glu Leu Tyr Arg 565 570 575 Gln Trp Thr Asp Arg Ile Met GluGlu Phe Phe Gln Gln Gly Asp Lys 580 585 590 Glu Arg Glu Arg Gly Met GluIle Ser Pro Met Cys Asp Lys His Thr 595 600 605 Ala Ser Val Glu Lys SerGln Val Gly Phe Ile Asp Tyr Ile Val His 610 615 620 Pro Leu Trp Glu ThrTrp Ala Asp Leu Val Gln Pro Asp Ala Gln Asp 625 630 635 640 Ile Leu AspThr Leu Glu Asp Asn Arg Asn Trp Tyr Gln Ser Met Ile 645 650 655 Pro GlnSer Pro Ser Pro Pro Leu Asp Glu Arg Ser Arg Asp Cys Gln 660 665 670 GlyLeu Met Glu Lys Phe Gln Phe Glu Leu Thr Leu Glu Glu Glu Asp 675 680 685Ser Glu Gly Pro Glu Lys Glu Gly Glu Gly Pro Asn Tyr Phe Ser Ser 690 695700 Thr Lys Thr Leu Cys Val Ile Asp Pro Glu Asn Arg Asp Ser Leu Glu 705710 715 720 Glu Thr Asp Ile Asp Ile Ala Thr Glu Asp Lys Ser Leu Ile AspThr 725 730 735 8 564 PRT Rattus norvegicus 8 Met Lys Glu Gln Gly GlyThr Val Ser Gly Ala Gly Ser Ser Arg Gly 1 5 10 15 Gly Gly Asp Ser AlaMet Ala Ser Leu Gln Pro Leu Gln Pro Asn Tyr 20 25 30 Leu Ser Val Cys LeuPhe Ala Glu Glu Ser Tyr Gln Lys Leu Ala Met 35 40 45 Glu Thr Leu Glu GluLeu Asp Trp Cys Leu Asp Gln Leu Glu Thr Ile 50 55 60 Gln Thr Tyr Arg SerVal Ser Glu Met Ala Ser Asn Lys Phe Lys Arg 65 70 75 80 Met Leu Asn ArgGlu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly 85 90 95 Asn Gln Val SerGlu Tyr Ile Ser Asn Thr Phe Leu Asp Lys Gln Asn 100 105 110 Asp Val GluIle Pro Ser Pro Thr Gln Lys Asp Arg Glu Lys Lys Lys 115 120 125 Lys GlnGln Leu Met Thr Gln Ile Ser Gly Val Lys Lys Leu Met His 130 135 140 SerSer Ser Leu Asn Asn Thr Ser Ile Ser Arg Phe Gly Val Asn Thr 145 150 155160 Glu Asn Glu Asp His Leu Ala Lys Glu Leu Glu Asp Leu Asn Lys Trp 165170 175 Gly Leu Asn Ile Phe Asn Val Ala Gly Tyr Ser His Asn Arg Pro Leu180 185 190 Thr Cys Ile Met Tyr Ala Ile Phe Gln Glu Arg Asp Leu Leu LysThr 195 200 205 Phe Lys Ile Ser Ser Asp Thr Phe Val Thr Tyr Met Met ThrLeu Glu 210 215 220 Asp His Tyr His Ser Asp Val Ala Tyr His Asn Ser LeuHis Ala Ala 225 230 235 240 Asp Val Ala Gln Ser Thr His Val Leu Leu SerThr Pro Ala Leu Asp 245 250 255 Ala Val Phe Thr Asp Leu Glu Ile Leu AlaAla Ile Phe Ala Ala Ala 260 265 270 Ile His Asp Val Asp His Pro Gly ValSer Asn Gln Phe Leu Ile Asn 275 280 285 Thr Asn Ser Glu Leu Ala Leu MetTyr Asn Asp Glu Ser Val Leu Glu 290 295 300 Asn His His Leu Ala Val GlyPhe Lys Leu Leu Gln Glu Glu His Cys 305 310 315 320 Asp Ile Phe Gln AsnLeu Thr Lys Lys Gln Arg Gln Thr Leu Arg Lys 325 330 335 Met Val Ile AspMet Val Leu Ala Thr Asp Met Ser Lys His Met Ser 340 345 350 Leu Leu AlaAsp Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr Ser 355 360 365 Ser GlyVal Leu Leu Leu Asp Asn Tyr Thr Asp Arg Ile Gln Val Leu 370 375 380 ArgAsn Met Val His Cys Ala Asp Leu Ser Asn Pro Thr Lys Ser Leu 385 390 395400 Glu Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu Glu Phe Phe Gln 405410 415 Gln Gly Asp Lys Glu Arg Glu Arg Gly Met Glu Ile Ser Pro Met Cys420 425 430 Asp Lys His Thr Ala Ser Val Glu Lys Ser Gln Val Gly Phe IleAsp 435 440 445 Tyr Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp Leu ValGln Pro 450 455 460 Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu Asp Asn ArgAsn Trp Tyr 465 470 475 480 Gln Ser Met Ile Pro Gln Ser Pro Ser Pro ProLeu Asp Glu Arg Ser 485 490 495 Arg Asp Cys Gln Gly Leu Met Glu Lys PheGln Phe Glu Leu Thr Leu 500 505 510 Glu Glu Glu Asp Ser Glu Gly Pro GluLys Glu Gly Glu Gly Pro Asn 515 520 525 Tyr Phe Ser Ser Thr Lys Thr LeuCys Val Ile Asp Pro Glu Asn Arg 530 535 540 Asp Ser Leu Glu Glu Thr AspIle Asp Ile Ala Thr Glu Asp Lys Ser 545 550 555 560 Leu Ile Asp Thr 9721 PRT Rattus norvegicus 9 Met Thr Ala Lys Asn Ser Ser Lys Glu Leu ProAla Ser Glu Ser Glu 1 5 10 15 Val Cys Ile Lys Thr Phe Lys Glu Gln MetArg Leu Glu Leu Glu Leu 20 25 30 Pro Lys Leu Pro Gly Asn Arg Pro Thr SerPro Lys Ile Ser Pro Arg 35 40 45 Ser Ser Pro Arg Asn Ser Pro Cys Phe PheArg Lys Leu Leu Val Asn 50 55 60 Lys Ser Ile Arg Gln Arg Arg Arg Phe ThrVal Ala His Thr Cys Phe 65 70 75 80 Asp Val Glu Asn Gly Pro Ser Pro GlyArg Ser Pro Leu Asp Pro Gln 85 90 95 Ala Ser Ser Ser Ser Gly Leu Val LeuHis Ala Ala Phe Pro Gly His 100 105 110 Ser Gln Arg Arg Glu Ser Phe LeuTyr Arg Ser Asp Ser Asp Tyr Asp 115 120 125 Leu Ser Pro Lys Ala Met SerArg Asn Ser Ser Leu Pro Ser Glu Gln 130 135 140 His Gly Asp Asp Leu IleVal Thr Pro Phe Ala Gln Val Leu Ala Ser 145 150 155 160 Leu Arg Ile ValArg Asn Asn Phe Thr Leu Leu Thr Asn Leu His Gly 165 170 175 Ala Pro AsnLys Arg Ser Pro Ala Ala Ser Gln Ala Pro Val Thr Arg 180 185 190 Val SerLeu Gln Glu Glu Ser Tyr Gln Lys Leu Ala Met Glu Thr Leu 195 200 205 GluGlu Leu Asp Trp Cys Leu Asp Gln Leu Glu Thr Ile Gln Thr Tyr 210 215 220Arg Ser Val Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu Asn 225 230235 240 Arg Glu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln Val245 250 255 Ser Glu Tyr Ile Ser Asn Thr Phe Leu Asp Lys Gln Asn Asp ValGlu 260 265 270 Ile Pro Ser Pro Thr Gln Lys Asp Arg Glu Lys Lys Lys LysGln Gln 275 280 285 Leu Met Thr Gln Ile Ser Gly Val Lys Lys Leu Met HisSer Ser Ser 290 295 300 Leu Asn Asn Thr Ser Ile Ser Arg Phe Gly Val AsnThr Glu Asn Glu 305 310 315 320 Asp His Leu Ala Lys Glu Leu Glu Asp LeuAsn Lys Trp Gly Leu Asn 325 330 335 Ile Phe Asn Val Ala Gly Tyr Ser HisAsn Arg Pro Leu Thr Cys Ile 340 345 350 Met Tyr Ala Ile Phe Gln Glu ArgAsp Leu Leu Lys Thr Phe Lys Ile 355 360 365 Ser Ser Asp Thr Phe Val ThrTyr Met Met Thr Leu Glu Asp His Tyr 370 375 380 His Ser Asp Val Ala TyrHis Asn Ser Leu His Ala Ala Asp Val Ala 385 390 395 400 Gln Ser Thr HisVal Leu Leu Ser Thr Pro Ala Leu Asp Ala Val Phe 405 410 415 Thr Asp LeuGlu Ile Leu Ala Ala Ile Phe Ala Ala Ala Ile His Asp 420 425 430 Val AspHis Pro Gly Val Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser 435 440 445 GluLeu Ala Leu Met Tyr Asn Asp Glu Ser Val Leu Glu Asn His His 450 455 460Leu Ala Val Gly Phe Lys Leu Leu Gln Glu Glu His Cys Asp Ile Phe 465 470475 480 Gln Asn Leu Thr Lys Lys Gln Arg Gln Thr Leu Arg Lys Met Val Ile485 490 495 Asp Met Val Leu Ala Thr Asp Met Ser Lys His Met Ser Leu LeuAla 500 505 510 Asp Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr Ser SerGly Val 515 520 525 Leu Leu Leu Asp Asn Tyr Thr Asp Arg Ile Gln Val LeuArg Asn Met 530 535 540 Val His Cys Ala Asp Leu Ser Asn Pro Thr Lys SerLeu Glu Leu Tyr 545 550 555 560 Arg Gln Trp Thr Asp Arg Ile Met Glu GluPhe Phe Gln Gln Gly Asp 565 570 575 Lys Glu Arg Glu Arg Gly Met Glu IleSer Pro Met Cys Asp Lys His 580 585 590 Thr Ala Ser Val Glu Lys Ser GlnVal Gly Phe Ile Asp Tyr Ile Val 595 600 605 His Pro Leu Trp Glu Thr TrpAla Asp Leu Val Gln Pro Asp Ala Gln 610 615 620 Asp Ile Leu Asp Thr LeuGlu Asp Asn Arg Asn Trp Tyr Gln Ser Met 625 630 635 640 Ile Pro Gln SerPro Ser Pro Pro Leu Asp Glu Arg Ser Arg Asp Cys 645 650 655 Gln Gly LeuMet Glu Lys Phe Gln Phe Glu Leu Thr Leu Glu Glu Glu 660 665 670 Asp SerGlu Gly Pro Glu Lys Glu Gly Glu Gly Pro Asn Tyr Phe Ser 675 680 685 SerThr Lys Thr Leu Cys Val Ile Asp Pro Glu Asn Arg Asp Ser Leu 690 695 700Glu Glu Thr Asp Ile Asp Ile Ala Thr Glu Asp Lys Ser Leu Ile Asp 705 710715 720 Thr 10 2647 DNA Rattus norvegicus 10 gtcttgtcat caggagacctcattttacct ctaggttaag ggagagaatc tatgaagaga 60 aaggaatagt ctgtgtctcggtcttgtccg ggtcagtgtt tctgagagct cacagtggcc 120 acctgaagca tttttccccagaatgaatga ctgccctgcc tgagaacaga agagccaaac 180 agttcccccc acatggccatagggagctgg tttcatttag aagaaaagca aagagagggg 240 aaagcctccc tcatttctcctccggacggc aaacattcag aaatgacatc acacacccca 300 cagccccggg atgactaaggcagaagtagc ctgagaaaac tctgctctgc cctgagtttt 360 agggcacagt tatgcagatgagcgtctggg cgcaggttcc cgccttcttc ctctgaggaa 420 gtttcttggt agatcactgacacctcatcc cggcgagggg gtgaaaactt ggcaccagcc 480 actccccctc ccgggcagagcaccagaaag agcttggaag caaggagtcg gcaagcaaac 540 aatgaaggag caagggggcaccgtcagtgg cgccgggagc agccgaggcg gaggagactc 600 ggctatggcc agcctgcagccgctgcagcc taactacctg tctgtgtgtt tgtttgcaga 660 agaatcatat cagaaactagcaatggagac gctggaggaa ctagactggt gcctagacca 720 gctagagacc atccagacctaccgctctgt cagcgagatg gcttcaaaca agttcaaaag 780 gatgctgaac cgggagctgacacacctctc agagatgagc agatcaggga accaagtgtc 840 tgaatacatt tcgaacacgttcttagacaa gcagaacgat gtggaaatcc catctcccac 900 ccagaaggac agggagaagaagaagaagca gcagctcatg acccagataa gtggagtgaa 960 gaaactgatg cacagctcaagcctgaacaa cacaagcatc tcacgctttg gagtcaacac 1020 ggaaaatgag gatcatctagccaaggagct ggaagacctg aacaaatggg gccttaacat 1080 cttcaacgtg gctgggtactcccataatcg gcccctcaca tgcatcatgt acgccatttt 1140 ccaggaaaga gaccttctaaagacgtttaa aatctcctcc gacaccttcg taacctacat 1200 gatgacttta gaagaccattaccattctga tgtggcgtat cacaacagcc tgcacgctgc 1260 tgacgtggcc cagtcaacgcacgttctcct ctctacgcca gcactggatg ctgtcttcac 1320 agacctggaa atcctggctgccatttttgc agctgccatc catgatgttg atcatcctgg 1380 agtctccaat cagtttctcatcaatacaaa ttccgaactt gctttgatgt ataatgacga 1440 atctgtgctg gaaaaccatcacctcgctgt gggattcaag ctccttcaag aggaacattg 1500 cgacatcttt cagaatcttaccaagaagca acgccagaca ctcaggaaaa tggtgattga 1560 catggtgtta gcaactgatatgtccaagca catgagcctc ctggctgacc ttaaaacgat 1620 ggtagaaacc aaaaaggtgacgagctccgg tgttctcctc ctggacaact atactgaccg 1680 gatacaggtt cttcgcaacatggtacattg tgcagacctg agcaacccta ccaagtcctt 1740 ggagttgtat cggcaatggactgatcgcat catggaggag tttttccaac agggagacaa 1800 agaacgggag aggggaatggagattagccc aatgtgtgat aaacacacag cttctgtgga 1860 aaagtcccag gttggtttcattgactacat tgtccatcca ttgtgggaga cctgggcaga 1920 cctggttcag cctgatgctcaagacatttt ggacacacta gaagataaca ggaactggta 1980 ccagagtatg attccccagagcccctctcc accactggac gagaggagca gggactgcca 2040 aggccttatg gagaagtttcagttcgaact gacccttgaa gaagaggatt ctgaaggacc 2100 ggaaaaggag ggagaaggccccaactattt cagcagcaca aagacacttt gtgtgatcga 2160 tccagagaac agggattctctggaagagac tgacatagac attgccacag aagacaagtc 2220 tctgatcgac acataatctccctctgtgtg gaggtgaaca ttctatcctt gacgagcatg 2280 ccagctgagt ggtagggcccacctaccaga gccaaggcct gcacaaaaca aaggccacct 2340 ggctttgcag ttacttgagtttggagccag aatgcaaggc cgtgaagcaa atagcagttc 2400 cgtgctgcct tgccttgccggcgagcttgg cgagacccgc agctgtagta gaagccagtt 2460 cccagcacag ctaaatggcttgaaaacaga ggacagaaag ctgagagatt gctctgcaat 2520 aggtgttgag gggctgtcccgacaggtgac tgaactcact aacaacttca tctataaatc 2580 tcacccatcc tgttgtctgccaacctgtgt gccttttttg taaaatgttt tcgtgtcttt 2640 gaaatgc 2647 11 3133DNA Rattus norvegicus 11 gaattcgcgc acgagagcac atgctggatg gactctggttccgccctttg tgcagacaaa 60 agtgactggg tggccaggct ttgcttactg tctgagttaatgaagcttgt ttgataaggt 120 tttctttcaa aaaaaaatta catataaagg atttatcaaaagccctcatg aatatttcat 180 gagttgatac attcggctga atggattcag tgagtctcagtgtgtaactt gcacacaagc 240 cccatccaca aggaggctgg tgacagagga agcactttggcgcattttca gaggcaaagg 300 cagcctgata aagctcctgt gacaggctga cttgccattctcccagtatg ctgctcttgc 360 tctgaagtgc tccaggattg gaaccatcac ggcttcccaaattagcctag gacgagtgtg 420 cggacccagc agccttttaa cctgcggcag tgcctttgctatgttcaaga ctgttgttgt 480 ggatggtgaa agctagcgcg ccacacgaga catgacagcaaaaaattctt ccaaagaact 540 tccagcttct gaatctgagg tttgcataaa gactttcaaggagcagatgc gcttggaact 600 tgagcttcca aagctaccag gaaacagacc tacatctcccaaaatttctc cacgcagttc 660 accaaggaat tcaccatgct ttttcagaaa gttgctggtgaataaaagca tccgacagcg 720 gcgtcgcttc actgtggctc atacatgctt tgatgtggaaaatggccctt ctccaggtcg 780 gagcccactg gaccctcaag ccagctcttc ttcaggactggtacttcatg ccgccttccc 840 tgggcacagc caacgcagag agtcttttct ctacagatccgacagcgact atgacttgtc 900 accaaaagcg atgtcaagga actcctcact tcccagcgaacaacacggcg atgacctgat 960 tgtcactcct tttgcccagg ttcttgccag cttgcgaatcgtaagaaaca atttcaccct 1020 gctgacaaac cttcacggag caccgaacaa gaggtcgccagcggctagtc aggctccagt 1080 caccagagtc agcctgcaag aagaatcata tcagaaactagcaatggaga cgctggagga 1140 actagactgg tgcctagacc agctagagac catccagacctaccgctctg tcagcgagat 1200 ggcttcaaac aagttcaaaa ggatgctgaa ccgggagctgacacacctct cagagatgag 1260 cagatcaggg aaccaagtgt ctgaatacat ttcgaacacgttcttagaca agcagaacga 1320 tgtggaaatc ccatctccca cccagaagga cagggagaagaagaagaagc agcagctcat 1380 gacccagata agtggagtga agaaactgat gcacagctcaagcctgaaca acacaagcat 1440 ctcacgcttt ggagtcaaca cggaaaatga ggatcatctagccaaggagc tggaagacct 1500 gaacaaatgg ggccttaaca tcttcaacgt ggctgggtactcccataatc ggcccctcac 1560 atgcatcatg tacgccattt tccaggaaag agaccttctaaagacgttta aaatctcctc 1620 cgacaccttc gtaacctaca tgatgacttt agaagaccattaccattctg atgtggcgta 1680 tcacaacagc ctgcacgctg ctgacgtggc ccagtcaacgcacgttctcc tctctacgcc 1740 agcactggat gctgtcttca cagacctgga aatcctggctgccatttttg cagctgccat 1800 ccatgatgtt gatcatcctg gagtctccaa tcagtttctcatcaatacaa attccgaact 1860 tgctttgatg tataatgacg aatctgtgct ggaaaaccatcacctcgctg tgggattcaa 1920 gctccttcaa gaggaacatt gcgacatctt tcagaatcttaccaagaagc aacgccagac 1980 actcaggaaa atggtgattg acatggtgtt agcaactgatatgtccaagc acatgagcct 2040 cctggctgac cttaaaacga tggtagaaac caaaaaggtgacgagctccg gtgttctcct 2100 cctggacaac tatactgacc ggatacaggt tcttcgcaacatggtacatt gtgcagacct 2160 gagcaaccct accaagtcct tggagttgta tcggcaatggactgatcgca tcatggagga 2220 gtttttccaa cagggagaca aagaacggga gaggggaatggagattagcc caatgtgtga 2280 taaacacaca gcttctgtgg aaaagtccca ggttggtttcattgactaca ttgtccatcc 2340 attgtgggag acctgggcag acctggttca gcctgatgctcaagacattt tggacacact 2400 agaagataac aggaactggt accagagtat gattccccagagcccctctc caccactgga 2460 cgagaggagc agggactgcc aaggccttat ggagaagtttcagttcgaac tgacccttga 2520 agaagaggat tctgaaggac cggaaaagga gggagaaggccccaactatt tcagcagcac 2580 aaagacactt tgtgtgatcg atccagagaa cagggattctctggaagaga ctgacataga 2640 cattgccaca gaagacaagt ctctgatcga cacataatctccctctgtgt ggaggtgaac 2700 attctatcct tgacgagcat gccagctgag tggtagggcccacctaccag agccaaggcc 2760 tgcacaaaac aaaggccacc tggctttgca gttacttgagtttggagcca gaatgcaagg 2820 ccgtgaagca aatagcagtt ccgtgctgcc ttgccttgccggcgagcttg gcgagacccg 2880 cagctgtagt agaagccagt tcccagcaca gctaaatggcttgaaaacag aggacagaaa 2940 gctgagagat tgctctgcaa taggtgttga ggggctgtcccgacaggtga ctgaactcac 3000 taacaacttc atctataaat ctcacccatc ctgttgtctgccaacctgtg tgcctttttt 3060 gtaaaatgtt ttcgtgtctt tgaaatgcct gttgaatatctagagtttag tacctccttc 3120 tacaaacttt ttt 3133

1. An isolated and purified nucleic acid molecule comprising nucleotidesencoding the amino acid sequence of SEQ ID NO:
 2. 2. The nucleic acidmolecule of claim 1, comprising nucleotides 262 to 2238 of SEQ ID NO: 1.3. The nucleic acid molecule of claim 1, wherein said nucleic acidmolecule is subcloned into a plasmid.
 4. The nucleic acid molecule ofclaim 1, wherein said nucleic acid molecule is subcloned into aprokaryotic or eukaryotic expression vector.
 5. The nucleic acidmolecule of claim 1, wherein said nucleic acid molecule is stably ortransiently incorporated into a prokaryotic or eukaryotic host cell. 6.An isolated and purified protein comprising the amino acid sequence ofSEQ ID NO:
 2. 7. An isolated and purified nucleic acid moleculecomprising nucleotides which code for the amino acid sequence of SEQ IDNO:
 4. 8. The nucleic acid molecule of claim 7, comprising thenucleotide sequence of SEQ ID NO:
 3. 9. An isolated and purified nucleicacid molecule comprising a nucleotide sequence that encodes an aminoacid sequence that is at least 90% identical to the amino acid sequenceof SEQ ID NO:
 4. 10. An isolated and purified nucleic acid moleculecomprising a nucleotide sequence that encodes an amino acid sequencethat is at least 75% identical to the amino acid sequence of SEQ ID NO:4.
 11. An isolated and purified peptide comprising the amino acidsequence of SEQ ID NO:
 4. 12. An antibody that specifically recognizesthe peptide of claim
 11. 13. An isolated and purified nucleic acidmolecule comprising nucleotides encoding the amino acid sequence of SEQID NO:
 6. 14. The nucleic acid molecule of claim 13, comprisingnucleotide 325 to 2532 of SEQ ID NO:
 5. 15. The nucleic acid molecule ofclaim 13, wherein said nucleic acid molecule is subcloned into aplasmid.
 16. The nucleic acid molecule of claim 13, wherein said nucleicacid molecule is subcloned into a prokaryotic or eukaryotic expressionvector.
 17. The nucleic acid molecule of claim 14, wherein said nucleicacid molecule is stably or transiently incorporated into a prokaryoticor eukaryotic host cell.
 18. An isolated and purified protein comprisingthe amino acid sequence of SEQ ID NO: 6.